12-6021960-C-A

Position:

• chr12-6021960-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000552.5(VWF):​c.3614G>T​(p.Arg1205Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1205H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.16

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a strand (size 3) in uniprot entity VWF_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000552.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6021960-C-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 12-6021960-C-A is Pathogenic according to our data. Variant chr12-6021960-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 100271.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-6021960-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3614G>T	p.Arg1205Leu	missense_variant	27/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3614G>T	p.Arg1205Leu	missense_variant	27/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3614G>T	p.Arg1205Leu	missense_variant	27/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-28026G>T		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

VWF-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

The VWF c.3614G>T variant is predicted to result in the amino acid substitution p.Arg1205Leu. This variant has been reported in individuals with Von Willebrand disease (Kakela et al. 2006. PubMed ID: 16321553; Veyradier et al. 2016. PubMed ID: 26986123). Different missense variants in the same codon (3613C>A,p.Arg1205Ser; 3613C>T,p.Arg1205Cysr; 3614G>A,p.Arg1205His) have been reported in individuals with Von Willebrand disease (Schneppenheim et al. 2000. PubMed ID: 10669167; Kakela et al. 2006. PubMed ID: 16321553; Millar et al. 2008. PubMed ID: 18449422) suggesting that substitution of amino acid residue p.Arg1205 is not tolerated. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.91	P
Vest4		0.85
MutPred		0.56		Gain of catalytic residue at A1202 (P = 0.0037);
MVP		0.76
MPC		0.83
ClinPred		0.90	D
GERP RS		3.9
Varity_R		0.29
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121964895; hg19: chr12-6131126;